Frequency of use and perceived helpfulness of wellness strategies for bipolar and unipolar depression.

BACKGROUND: The majority of research in mood disorders has focused on pharmacologic, psychotherapeutic, and brain stimulation interventions. Conversely, the utility of less structured interventions, such as lifestyle modifications or wellness strategies, has remained understudied. The objective of the current study is to evaluate the frequency of use and perceived helpfulness of wellness strategies for bipolar and unipolar depression. METHODS: The Depression and Bipolar Support Alliance (DBSA) conducted an online survey asking participants about the use and helpfulness of wellness strategies. RESULTS: In total, 896 participants completed the survey (unipolar depression [n = 447] and bipolar depression [n = 449]). Wellness strategies were used by 62% and 59% of individuals with bipolar and unipolar depression, respectively. Listening to music, socializing, and adequate sleep were commonly reported wellness strategies. The majority of participants reported wellness strategies to be helpful. Use of wellness strategies was associated with greater overall perceived treatment effectiveness (P < .0001) and greater subjective helpfulness of medications (P = .039), psychotherapy (P < .0001), and peer support groups (P < .0001). CONCLUSIONS: Wellness strategies were commonly used by the majority of respondents. These strategies were subjectively helpful for most respondents and were associated with greater overall treatment effectiveness and increased helpfulness of medications, psychotherapy, and peer support groups. As such, wellness strategies should be considered while developing a holistic treatment plan for depression. Further research is needed to evaluate the antidepressant effects of specific wellness strategies to better understand the role of these interventions in the management of depression.

Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Association between therapeutic alliance, care satisfaction, and pharmacological adherence in bipolar disorder.

OBJECTIVES: We sought to understand the association of specific aspects of care satisfaction, such as patients' perceived relationship with their psychiatrist and access to their psychiatrist and staff, and therapeutic alliance with participants' likelihood to adhere to their medication regimens among patients with bipolar disorder. METHODS: We examined data from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder, an effectiveness study investigating the course and treatment of bipolar disorder. We expected that participants (n = 3037) with positive perceptions of their relationship with their psychiatrist and quality of psychopharmacologic care, as assessed by the Helping Alliance Questionnaire and Care Satisfaction Questionnaire, would be associated with better medication adherence. We utilized logistic regression models controlling for already established factors associated with poor adherence. RESULTS: Patients' perceptions of collaboration, empathy, and accessibility were significantly associated with adherence to treatment in individuals with bipolar disorder completing at least 1 assessment. Patients' perceptions of their psychiatrists' experience, as well as of their degree of discussing medication risks and benefits, were not associated with medication adherence. CONCLUSIONS: Patients' perceived therapeutic alliance and treatment environment impact their adherence to pharmacotherapy recommendations. This study may enable psychopharmacologists' practices to be structured to maximize features associated with greater medication adherence.

Cariprazine for the Adjunctive Treatment of Major Depressive Disorder in Patients With Inadequate Response to Antidepressant Therapy: Results of a Randomized, Double-Blind, Placebo-Controlled Study.

Objective: To assess the efficacy of cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, as adjunctive treatment for patients with major depressive disorder (MDD) and inadequate response to ongoing antidepressant therapy (ADT).Methods: This randomized, double-blind, placebo-controlled study was conducted from November 2018 to September 2021. Adults with MDD per DSM-5 criteria were randomized (1:1:1) to cariprazine 1.5 mg/d or 3 mg/d plus ADT, or placebo plus ADT. The primary and secondary endpoints were change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score and Clinical Global Impressions-Severity of Illness (CGI-S) score, respectively.Results: A total of 249 placebo-, 250 cariprazine 1.5 mg/d-, and 251 cariprazine 3 mg/d-treated patients were included in the modified intent-to-treat population. At week 6, the least squares mean change in MADRS total score was -13.8 for cariprazine 1.5 mg/d, -14.8 for cariprazine 3 mg/d, and -13.4 for placebo; differences versus placebo were not statistically significant. Mean change from baseline in CGI-S scores at week 6 was not significant for cariprazine versus placebo, although a trend toward significance was observed for 3 mg/d (P = .0573 [not adjusted for multiplicity]). Common treatment-emergent adverse events (≥ 5% either cariprazine group and twice placebo) were akathisia and insomnia.Conclusions: There were no statistically significant differences for cariprazine 1.5 or 3 mg/d versus placebo on the primary or secondary outcomes. Cariprazine was generally well tolerated, and no new safety concerns were detected.Clinical Trials Registration: ClinicalTrials.gov identifier NCT03739203.

Adjunctive Cariprazine for the Treatment of Patients With Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

OBJECTIVE: The purpose of this study was to investigate the efficacy of cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, as adjunctive therapy for patients with major depressive disorder and nonresponse to at least one antidepressant monotherapy. METHODS: In this double-blind placebo-controlled study, adults with major depressive disorder and inadequate response to antidepressants alone were randomized in a 1:1:1 ratio to placebo, cariprazine at 1.5 mg/day, or cariprazine at 3.0 mg/day. The primary outcome was change from baseline to week 6 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Least-squares mean differences were estimated in the modified intent-to-treat (mITT) population using a mixed-effects model for repeated measures with adjustment for multiple comparisons. RESULTS: The mITT population comprised 751 patients (placebo: N=249; cariprazine 1.5 mg/day: N=250; cariprazine 3.0 mg/day: N=252). At week 6, the mean reduction from baseline in MADRS total score was significantly greater with cariprazine 1.5 mg/day than with placebo (-14.1 vs. -11.5) but not with cariprazine 3.0 mg/day (-13.1). Significant differences between the cariprazine 1.5 mg/day and placebo groups were also observed at weeks 2 and 4. Meeting the MADRS response criteria was significantly more likely among patients receiving cariprazine 1.5 mg/day than placebo (44.0% vs. 34.9%); remission rates were not significantly different among groups. Common treatment-emergent adverse events (≥5% in either cariprazine group and twice the placebo rate) were akathisia and nausea. CONCLUSIONS: Adjunctive cariprazine at 1.5 mg/day demonstrated efficacy in reducing depressive symptoms in adults with major depressive disorder and inadequate response to antidepressants alone. Cariprazine was generally well tolerated, with a safety profile that was consistent with previous findings.

Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial.

OBJECTIVE: In a phase 3 randomized double-blind placebo-controlled study, the authors investigated the efficacy and safety of 42 mg/day of lumateperone in patients with bipolar I or bipolar II disorder experiencing a major depressive episode. METHODS: Patients 18-75 years old with a clinical diagnosis of bipolar I or bipolar II disorder and experiencing a major depressive episode were eligible for the study. Patients were randomized in a 1:1 ratio to receive 42 mg/day of lumateperone (N=188) or placebo (N=189), administered orally once daily in the evening for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to day 43 in score on the Montgomery-Åsberg Depression Rating Scale (MADRS) and total score on the Clinical Global Impressions Scale-Bipolar Version severity scale (CGI-BP-S), respectively. Safety assessments included treatment-emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms, and suicidality. RESULTS: At day 43, lumateperone treatment was associated with significantly greater improvement from baseline in MADRS score compared with placebo (least squares mean difference compared with placebo, -4.6 points; effect size=-0.56) and CGI-BP-S total score (least squares mean difference compared with placebo, -0.9; effect size=-0.46). Significant MADRS superiority for lumateperone over placebo was observed both in patients with bipolar I and bipolar II disorders. Somnolence and nausea were the only treatment-emergent adverse events that occurred with lumateperone at a clinically meaningful greater rate than placebo. The incidence of extrapyramidal symptom-related treatment-emergent adverse events was low and similar to that for placebo. Minimal changes were observed in weight, vital signs, or metabolic or endocrine assessments. CONCLUSIONS: Lumateperone at 42 mg/day significantly improved depression symptoms and was generally well tolerated in patients with major depressive episodes associated with both bipolar I and bipolar II disorders.

Effectiveness of adjunctive antidepressant treatment for bipolar depression.

BACKGROUND: Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania. METHODS: In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined. RESULTS: Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups. CONCLUSIONS: The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

The interactive computer interview for mania.

OBJECTIVES: The Interactive Computer Interview for Mania (ICI-M) is a computer-administered interview that presents probes to assess symptom severity and utilizes a scoring algorithm to select follow-up questions and rate subject responses in accordance with rating scale anchor points. The current study examines the acceptability, feasibility, and reliability of the ICI-M as a potential method for evaluating the performance of human raters. METHODS: Participants with a diagnosis of bipolar I or II disorder completed both a live interview of the Young Mania Rating Scale with a human rater (LR) and the ICI-M. A panel of three expert raters reviewed each videotaped LR and assigned a consensus rating (CR). Participants completed a modified version of the Client Satisfaction Questionnaire to assess each method. RESULTS: Intraclass correlation coefficients were 0.91 between the ICI-M and CR and 0.97 between the LR and CR (n = 100), providing empirical support for the inter-rater reliability of each approach. Coefficient alphas indicated comparable internal consistency reliability: ICI-M = 0.82, LR = 0.83, and CR = 0.84. The ICI-M was significantly more sensitive in detecting symptomatology than the LR (p < 0.001) and the CR (p < 0.001), and resulted in significantly higher ratings than CR on mood, speech, psychotic content, and disruptive-aggressive behavior. While participants endorsed significantly higher overall satisfaction with LR, no significant differences emerged between ICI-M and LR regarding willingness to participate again or ability to understand the questions. CONCLUSIONS: The ICI-M is a well-accepted and reliable method for assessing manic symptoms. The ICI-M is a tool with adequate sensitivity to elicit symptoms and rate severity and is recommended as a tool to monitor and improve rater performance, not as a replacement of a human rater.

Phenotypic effects of a bipolar liability gene among individuals with major depressive disorder.

Variations in voltage-dependent calcium channel L-type, alpha 1C subunit (CACNA1C) gene have been associated with bipolar disorder in a recent meta-analysis of genome-wide association studies [Ferreira et al., 2008]. The impact of these variations on other psychiatric disorders has not been yet investigated. Caucasian non-Hispanic participants in the STAR*D study of treatment for depression for whom DNA was available (N = 1213) were genotyped at two single-nucleotide polymorphisms (SNPs) (rs10848635 and rs1006737) in the CACNA1C gene. We examined putative phenotypic indicators of bipolarity among patients with major depression and elements of longitudinal course suggestive of latent bipolarity. We also considered remission and depression severity following citalopram treatment. The rs10848635 risk allele was significantly associated with lower levels of baseline agitation (P = 0.03; beta = -0.09). The rs1006737 risk allele was significantly associated with lesser baseline depression severity (P = 0.04; beta = -0.4) and decreased likelihood of insomnia (P = 0.047; beta = -0.22). Both markers were associated with an increased risk of citalopram-emergent suicidality (rs10848635: OR = 1.29, P = 0.04; rs1006737: OR = 1.34, P = 0.02). In this exploratory analysis, treatment-emergent suicidality was associated with two risk alleles in a putative bipolar liability gene.

Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus.

We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.

The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments.

OBJECTIVES: Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. METHODS: These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. RESULTS: General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. CONCLUSIONS: These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice.

Cigarette smoking is associated with suicidality in bipolar disorder.

OBJECTIVES: Cigarette smoking in individuals with bipolar disorder has been associated with suicidal behavior, although the precise relationship between the two remains unclear. METHODS: In this prospective observational study of 116 individuals with bipolar disorder, we examined the association between smoking and suicidality as measured by Linehan's Suicide Behaviors Questionnaire (SBQ) and prospective suicide attempts over a nine-month period. Impulsivity was measured by the Barratt Impulsiveness Scale. RESULTS: Smoking was associated with higher baseline SBQ scores in univariate and adjusted analyses, but was not significant after statistical adjustment for impulsivity in a regression model. A higher proportion of smokers at baseline made a suicide attempt during the follow-up period (5/31, 16.1%) compared to nonsmokers (3/85, 3.5%); p = 0.031, odds ratio = 5.25 (95% confidence interval: 1.2-23.5). Smoking at baseline also significantly predicted higher SBQ score at nine months. CONCLUSIONS: In this study, current cigarette smoking was a predictor of current and nine-month suicidal ideation and behavior in bipolar disorder, and it is likely that impulsivity accounts for some of this relationship.

Stability of symptoms across major depressive episodes in bipolar disorder.

OBJECTIVE: Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated. METHODS: We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression. RESULTS: A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes. CONCLUSION: While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.

The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders.

OBJECTIVES: Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes. METHODS: Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders. RESULTS: Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions. CONCLUSION: Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia.

OBJECTIVE: Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders. METHODS: We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS). RESULTS: Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL. CONCLUSIONS: Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.

Brain GABA levels in patients with bipolar disorder.

PURPOSE: A growing body of research supports an important role for GABA in the pathophysiology of bipolar and other mood disorders. The purpose of the current study was to directly examine brain GABA levels in a clinical sample of bipolar patients. GENERAL METHODS: We used magnetic resonance spectroscopy (MRS) to examine whole brain and regional GABA, glutamate and glutamine in 13 patients with bipolar disorder compared to a matched group of 11 healthy controls. FINDINGS: There were no significant differences in GABA, glutamate or glutamine between patients and controls. CONCLUSIONS: Further research is needed to better characterize the GABAergic and glutamatergic effects of pharmacotherapy, anxiety comorbidity and clinical state in bipolar disorder.

Increasing minority research participation through collaboration with community outpatient clinics: the STEP-BD Community Partners Experience.

BACKGROUND: Minority populations have been under-represented in mental health research studies. The systematic treatment enhancement program for bipolar disorder developed the Community Partners Program (CPP) to address this issue in a large, prospective treatment study of persons with bipolar disorder. PURPOSE: The primary goal of CPP was to develop a community-based infrastructure for studying bipolar disorder that would enhance the ethnic/racial and socioeconomic diversity of participants. METHODS: Selected academic sites partnered with local clinics (n = 6 partnerships in five cities). This report describes the conceptualization, implementation, and qualitative evaluation of CPP, as well as quantitative analysis of clinical and sociodemographic differences between the samples recruited at academic versus community sites. RESULTS: Quantitative analysis of the 155 participants from the six partnerships revealed enrollment of 45% from minority populations (vs. 15% in academic sites). Significant sociodemographic differences were evident not only between academic and community sites, but within minority and non-minority groups across site types. Notably, clinical differences were not evident between participants from academic and community sites. Review of qualitative data suggests that certain factors around implementation of research protocols may enhance community participation. CONCLUSIONS: Moving research recruitment and participation into community sites was more successful in increasing minority enrollment than efforts to attract such individuals to academic sites. Recommendations for creating and maintaining academic/community partnerships are given. LIMITATIONS: Several important variables were not considered including mood severity, hospitalization, or treatment differences. Minority participants were grouped by combining African American and Hispanics, which may have obscured subgroup differences. A derivation of standard qualitative methods was used in this study.

Treatment effectiveness and tolerability outcomes that are most important to individuals with bipolar and unipolar depression.

OBJECTIVE: To evaluate patient-reported determinants of treatment effectiveness and tolerability amongst persons with major depressive or bipolar disorders. METHODS: The Depression and Bipolar Support Alliance (DBSA) conducted an online survey February 2016-April 2016 asking participants about which outcomes are most important in determining subjective treatment effectiveness and tolerability. RESULTS: In total, 896 participants completed the survey [49.9% unipolar depression (n = 447) and 50.1% bipolar depression (n = 449)]. Survey respondents reported several previous medication trials with the minority (25% of depression and 29% of bipolar group) of respondents reporting that their current treatment plan was completely effective. When asked how they know that the treatment is working, for both groups, the highest rated response was, "I don't feel overly anxious, agitated or irritable." Weight gain was the adverse effect that most commonly led respondents to discontinue a medication. Lethargy, emotional blunting, shaking/trembling and anxiety were also identified as common treatment-emergent experiences leading to medication discontinuation in greater than one-third of respondents. The bipolar group more frequently identified several signs that suggested treatment was working (e.g., improved neurocognitive function, improved sleep), as well as more frequently reported several reasons to discontinue medications (e.g., weight gain, trembling). CONCLUSION: Numerous factors emerged as important to patients when evaluating treatment effectiveness and tolerability. Some of these factors are inadequately assessed by current standard clinical trial outcome measures. Considering these important patient-centred outcomes in future clinical trials, treatment guidelines and direct patient care may serve to improve patient satisfaction, quality of life and the therapeutic alliance.

Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study.

OBJECTIVE: Cariprazine, a dopamine D3/D2 and 5-HT1A receptor partial agonist, was found to be effective in treating bipolar I depression in a previous phase 2 study. This phase 3 study further assessed the efficacy, safety, and tolerability of cariprazine in bipolar I depression. METHODS: In a double-blind placebo-controlled study, adult participants (18-65 years old) who met DSM-5 criteria for bipolar I disorder and a current depressive episode were randomly assigned to receive placebo (N=158) or cariprazine at 1.5 mg/day (N=157) or 3.0 mg/day (N=165). The primary and secondary efficacy parameters were changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score, respectively. Least squares mean differences were estimated using a mixed model for repeated measures, and p values were adjusted for multiplicity. RESULTS: Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms (reducing MADRS total score); the least squares mean differences were -2.5 (95% CI=-4.6, -0.4) for cariprazine at 1.5 mg/day and -3.0 (95% CI=-5.1, -0.9) for cariprazine at 3.0 mg/day. Both cariprazine dosages were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance after adjustment for multiplicity (least squares mean difference, -0.2 [95% CI=-0.5, 0.0] for the 1.5 mg/day group and -0.3 [95% CI=-0.5, 0.0] for the 3.0 mg/day group). Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable across groups. CONCLUSIONS: Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.

The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD.

OBJECTIVE: In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of demographic, phenomenological, and clinical variables, including antidepressant use, to prospectively observed mood episode frequency. METHOD: For 1,742 bipolar I and II patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), episodes of mood disorders were evaluated for up to 1 year of treatment. RESULTS: At entry, 32% of the patients met the DSM-IV criteria for rapid cycling in the prestudy year. Of the 1,742 patients, 551 (32%) did not complete 1 year of treatment. Among the 1,191 patients remaining, those with prior rapid cycling (N=356) were more likely to have further recurrences, although not necessarily more than four episodes per year. At the end of 12 months, only 5% (N=58) of the patients could be classified as rapid cyclers; 34% (N=409) had no further mood episodes, 34% (N=402) experienced one episode, and 27% (N=322) had two or three episodes. Patients who entered the study with earlier illness onset and greater severity were more likely to have one or more episodes in the prospective study year. Antidepressant use during follow-up was associated with more frequent mood episodes. CONCLUSIONS: While DSM-IV rapid cycling was prospectively observed in only a small percentage of patients, the majority of these patients had continued recurrences at lower but clinically significant rates. This suggests that cycling is on a continuum and that prevention of recurrences may require early intervention and restricted use of antidepressants.